Azeliragon + Chemoradiotherapy for Glioblastoma

Overseen By Jiayi Huang, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Washington University School of Medicine

Must be taking: Temozolomide

Must not be taking: CYP 2C8 inhibitors

Disqualifiers: Prior cranial RT, IDH mutation, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

12 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot take CYP 2C8 inhibitors within 2 weeks before joining the study. It's best to discuss your current medications with the study team.

What data supports the effectiveness of the treatment Azeliragon + Chemoradiotherapy for Glioblastoma?

Research shows that radiation therapy is effective in treating glioblastoma, and combining it with chemotherapy can improve outcomes compared to radiation alone. Although Azeliragon is not specifically mentioned, the combination approach is supported by evidence of improved survival rates in similar treatments. ^{1 2 3 4 5}

What makes the Azeliragon + Chemoradiotherapy treatment unique for glioblastoma?

Azeliragon combined with chemoradiotherapy for glioblastoma is unique because it introduces a novel drug, Azeliragon, which may work differently from standard treatments like temozolomide by targeting specific pathways involved in the disease. This combination could potentially enhance the effectiveness of radiation therapy, offering a new approach for patients with this aggressive brain cancer. ^{5 6 7 8 9}

What is the purpose of this trial?

Preclinical data have demonstrated the combination of azeliragon, a RAGE inhibitor, with radiation therapy (RT) can effectively reduce immune-suppressive myeloid cells and restore T-cell activation to improve tumor control in murine glioma models. Ongoing clinical studies of azeliragon with RT alone and RT plus temozolomide (TMZ) to treat patients with newly diagnosed glioblastoma (GBM) have demonstrated safety and tolerability. The purpose of this window-of-opportunity study is to validate that the combination of azeliragon with RT and TMZ would modulate immune-suppressive myeloid and T cells in the tumor microenvironment in patients with GBM.

Research Team

Jiayi Huang, M.D.

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

This trial is for patients with a new diagnosis of glioblastoma, which is an aggressive type of brain tumor. Participants should be suitable for surgery or laser interstitial thermal therapy (LITT), and ready to undergo radiation therapy and take the drug Temozolomide. Specific inclusion and exclusion criteria details are not provided.

Inclusion Criteria

I am willing to undergo surgery to remove or treat the tumor after chemoradiotherapy.

I can care for myself but may need occasional help.

Females of childbearing potential must be willing to use an acceptable method of birth control during the trial and for 6 months after the last administration of azeliragon

Exclusion Criteria

My cancer has spread to the lining of the brain or other areas.

Patients with concurrent participation in another interventional clinical trial or use of another investigational agent within 30 days prior to study entry

I haven't taken CYP 2C8 inhibitors in the last 2 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Chemoradiotherapy

Participants receive fractionated radiation therapy (RT) to 60 Gy in 30 daily fractions with concurrent Temozolomide (TMZ) and, in some arms, Azeliragon

6 weeks

Surgery or LITT

Participants undergo planned surgery of either resection or Laser Interstitial Thermal Therapy (LITT) 1 month after completion of RT

1 month

Adjuvant Therapy

Participants receive adjuvant Temozolomide (TMZ) and Azeliragon for up to 6 months

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Azeliragon
• Radiation therapy

Trial Overview The study tests if adding Azeliragon, a drug that inhibits RAGE (a receptor involved in inflammation), to standard treatment with radiation and Temozolomide can make the immune system better at controlling tumor growth in glioblastoma patients.

Participant Groups

Group I: Arm 2: Neoadjuvant RT, Temozolomide (TMZ) & Azeliragon + Surgery or LITT + Adjuvant TMZ & Azeliragon Experimental Treatment 4 Interventions

RT will consist of fractionated RT to 60 Gy in 30 daily fractions administered per standard of care RTOG approach. Concurrent TMZ during RT will be self-administered by mouth (PO) as per standard of care. Patients will receive azeliragon as well. Azeliragon is self-administered PO. Azeliragon dosing will consist of 6 days of a loading dose of 30 mg twice per day (days 1-6), followed by 20 mg daily starting on the 7th day. RT should ideally start on day 7, but may start up to day 21. Azeliragon should continue until the day before planned surgical procedure. 1 month after completion of RT, patient will proceed with planned surgery of either resection or LITT. Patients will then receive adjuvant TMZ and azeliragon for up to 6 months. Patient should start with the loading dose 30 mg BID for 6 days before the start of adjuvant TMZ. After 6 days, azeliragon 20 mg once daily should be continued in combination with TMZ. TMZ should ideally start on day 7, but may start up to day 21.

Group II: Arm 1: Neoadjuvant RT and Temozolomide (TMZ) + Surgery or LITT + Adjuvant TMZ & Azeliragon Active Control 4 Interventions

Radiation therapy (RT) will consist of fractionated RT to 60 Gy in 30 daily fractions administered per standard of care RTOG approach. Concurrent TMZ during RT will be self-administered by mouth (PO) as per standard of care. 1 month after completion of RT, patient will proceed with planned surgery of either resection or LITT. Patients will then receive adjuvant TMZ and azeliragon for up to 6 months. Patient should start with the loading dose 30 mg BID for 6 days before the start of adjuvant TMZ. After 6 days, azeliragon 20 mg once daily should be continued in combination with TMZ. TMZ should ideally start on day 7, but may start up to day 21.

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Cantex Pharmaceuticals

Industry Sponsor

Trials

14

Recruited

390+

Findings from Research

In a study of 126 newly diagnosed glioblastoma patients, both standard dose radiotherapy (SDRT) and escalated dose radiotherapy (EDRT) combined with temozolomide (TMZ) showed similar overall survival (OS) and local progression-free survival (LPFS), with no statistically significant differences between the two treatments.

While the EDRT group had a median OS of 22 months compared to 14.9 months for SDRT, this difference was not statistically significant, indicating that further research with larger populations is needed to determine the true efficacy of EDRT in combination with TMZ.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective comparison of standard and escalated doses of radiotherapy in newly diagnosed glioblastoma patients treated with concurrent and adjuvant temozolomide. Guler, OC., Yıldırım, BA., Önal, C., et al.[2019]

Temozolomide (TMZ) was found to effectively radiosensitize two out of three human glioblastoma multiforme (GBM) cell lines when combined with single-dose gamma-irradiation, indicating its potential to enhance the effectiveness of radiation therapy.

In a study involving three genetically characterized GBM cell lines, TMZ demonstrated an additive effect with fractionated irradiation, particularly showing a significant reduction in surviving cells in the AMC 3046 cell line, suggesting that TMZ can improve treatment outcomes for certain GBM patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential radiosensitizing potential of temozolomide in MGMT promoter methylated glioblastoma multiforme cell lines. van Nifterik, KA., van den Berg, J., Stalpers, LJ., et al.[2018]

In a study involving 16 patients with newly diagnosed glioblastoma multiforme, the combination of intensity-modulated radiotherapy (IMRT) and temozolomide (TMZ) was found to be tolerable, with a median survival of 16.2 months, indicating potential efficacy in this patient population.

The study demonstrated that escalating the IMRT dose to 6 Gy per fraction was achievable without reaching the maximal tolerated dose, suggesting that higher doses may be safely administered in selected patients with smaller tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of hypofractionated intensity-modulated radiotherapy with temozolomide chemotherapy for patients with newly diagnosed glioblastoma multiforme. Chen, C., Damek, D., Gaspar, LE., et al.[2018]

In a phase II trial involving 265 patients with newly diagnosed glioblastoma and unmethylated MGMT promoter, the standard cilengitide regimen showed a median overall survival of 16.3 months, which was significantly better than the control arm's 13.4 months.

Both cilengitide regimens were well tolerated, but the study's inconsistent survival outcomes and limited sample size made it difficult to draw firm conclusions about the clinical efficacy of cilengitide in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study. Nabors, LB., Fink, KL., Mikkelsen, T., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Efficacy of sequential radiation and chemotherapy in treating glioblastoma with poor performance status. [2020]

2. France pubmed.ncbi.nlm.nih.gov

[Radiotherapy of glioblastoma]. [2019]

3. Australia pubmed.ncbi.nlm.nih.gov

Patterns of failure for glioblastoma multiforme following concurrent radiation and temozolomide. [2022]

4. India pubmed.ncbi.nlm.nih.gov

Retrospective comparison of standard and escalated doses of radiotherapy in newly diagnosed glioblastoma patients treated with concurrent and adjuvant temozolomide. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Concurrent chemoradiotherapy and adjuvant chemotherapy with Topotecan for patients with glioblastoma multiforme. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Phase 2 Study of Radiation Therapy Plus Low-Dose Temozolomide Followed by Temozolomide and Irinotecan for Glioblastoma: NRG Oncology RTOG Trial 0420. [2020]

7. United States pubmed.ncbi.nlm.nih.gov

Differential radiosensitizing potential of temozolomide in MGMT promoter methylated glioblastoma multiforme cell lines. [2018]

8. United States pubmed.ncbi.nlm.nih.gov

Phase I trial of hypofractionated intensity-modulated radiotherapy with temozolomide chemotherapy for patients with newly diagnosed glioblastoma multiforme. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study. [2022]